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US 8,263,612 B2Granted
Viral inhibitors
AssigneesGilead Sciences, Inc., K.U. Leuven Research & Development, Gerhard Puerstinger
InventorsSteven S. Bondy, David A. Oare, Gerhard Puerstinger
Life of this patent
Estimating the term…
Abstract
Pyrrolo[2,3-c]pyridine or pyrrolo[3,2-c]pyridine compounds having the general formula (A), wherein the dashed lines, X, Y and R1 through R5 are as defined in the specification. The compounds are useful in the prophylaxis or treatment of viral infections.
Claims18
A compound having the general formula (A),
- wherein:
- the dotted lines represent at least 3, optionally 4 double bonds, provided that no two double bonds are adjacent to one another;
- A is —N═ and the other one A is CR26;
- R1 is selected from hydrogen, aryl, heterocycle, C1-C10 alkoxy, thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkyl-amino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
- Y is selected from a single bond, O, S(O)m, NR10, alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein 1 to 3-C(H)═, —C(≡) or —CH2— groups of each alkylene, alkenylene or alkynylene optionally are independently replaced with a heteroatom or heteroatom group selected from —O—, ═O, —OR27, —S—, ═S, —SR27, —NR27, —N(R27)2, where R27 independently is hydrogen, C1-18 alkyl, C2-18 alkenyl, or C2-18 alkynyl;
- provided that YR1 is not hydrogen or C1-6 alkyl;
- R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C3-10 cycloalkynyl, or heterocycle;
- X is absent or is selected from hydrogen, alkylene, C2-10 alkenylene or C2-10 alkynylene, wherein 1 to 3 —C(H)═, —C(≡) or —CH2— groups of each alkylene, alkenylene or alkynylene optionally are independently replaced with a heteroatom or heteroatom group selected from —O—, ═O, —OR27, —S—, ═S, —SR27, —NR27, —N(R27)2, where R27 independently is hydrogen, C1-18 alkyl, C2-18 alkenyl, or C2-18 alkynyl;
- m is any integer from 0 to 2;
- R3 is absent or is selected from hydrogen, aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl-N(R10)—, or an aromatic heterocycle, where each said substituent is optionally substituted with 1 or more R17, provided that for cycloalkenyl the double bond is not adjacent to a nitrogen;
- R5 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocycle;
- R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocycle and C1-18 hydroxyalkyl, where each is optionally substituted with 1 to 3 R19;
- R7 and R8 are independently selected from hydrogen, C1-18 alkyl, C1-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12;
- —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or R7 and R8 are taken together with the nitrogen to form a heterocycle;
- R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2OC(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
- R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocycle, or an amino acid residue;
- R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
- R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
- R17 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halogenated alkyl, C2-18 halogenated alkenyl, C2-18 halogenated alkynyl, C1-18 halogenated alkoxy, C1-18 halogenated alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, CO2H CO2R18, NO2, NR7R8, haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, C1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, or C1-18 hydroxyalkyl is optionally substituted with 1 or more R19;
- R19 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR20R21, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio or aryl(C1-18)alkyl, where each is optionally substituted with 1 to 3 of ═O, NR20R21, ON, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R17 by alkyl, alkoxyalkoxy or halogen;
- R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
- R26 is independently selected from hydrogen, and C3-10 cycloalkyl;
- and salts, tautomers, and stereoisomers thereof.
20 more elements
A compound having the general formula:
- wherein:
- one A is —N═, and the other A is ═CR26;
- R1 is phenyl or an aromatic heterocycle with 5 or 6 ring atoms with either 1, 2 or 3 N, O or S atoms in the ring, and wherein each is optionally substituted with 1 or more R6;
- R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C3-10 cycloalkynyl, or heterocycle;
- X is C1-C10 alkylene, wherein 1 to 3 —CH2— groups optionally are independently replaced with a heteroatom or heteroatom group selected from —O—, ═O, —OR27, —NR27, and —N(R27)2, where R27 independently is hydrogen, C1-18 alkyl, C2-18 alkenyl, or C2-18 alkynyl;
- R3 is absent or is selected from hydrogen, aryl, and an aromatic heterocycle, where the aryl or heterocyclic groups are each optionally substituted with 1 or more R17;
- R5 is selected from hydrogen;
- C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocycle;
- R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocycle and C1-18 hydroxyalkyl, where each is optionally substituted with 1 to 3 R19;
- R7 and R8 are independently selected from hydrogen, C1-18 alkyl, C1-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12;
- —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or R7 and R8 are taken together with the nitrogen to form a heterocycle;
- R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2OC(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
- R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
- R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
- R17 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halogenated alkyl, C2-18 halogenated alkenyl, C2-18 halogenated alkynyl, C1-18 halogenated alkoxy, C1-18 halogenated alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, CO2H, CO2R18, NO2, NR7R8, haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, C1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, or C1-18 hydroxyalkyl is optionally substituted with 1 or more R19;
- R19 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR20R21, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18 alkyl)oxy, arylthio, aryl(C1-18)alkylthio or aryl(C1-18)alkyl, where each is optionally substituted with 1 to 3 of ═O, NR20R21, CN, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R17 by alkyl, alkoxyalkoxy or halogen;
- R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
- R26 is independently selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, aryl, heterocycle, where each is optionally independently substituted with 1 to 3 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH;
- and pharmaceutically acceptable salts, and stereoisomers thereof.
16 more elements
A compound having the general formula:
- wherein:
- one A is —N═, and the other A is ═CR26;
- R1 is phenyl optionally substituted with 1 or 2 halogens;
- X is C1-C3 alkylene, wherein 1 or 2 —CH2— groups optionally are independently replaced with —O—, ═O, —OR27, —NR27, or —N(R27)2, where R27 independently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
- R3 is absent or is selected from hydrogen, phenyl, and an aromatic heterocycle with 5 or 6 ring atoms with either 1, 2 or 3 N, 1 N and 1 O, or 1 or 2 N and 1 S atoms in the ring, where the phenyl or heterocyclic groups are each optionally substituted with 1 or more R17;
- R17 is halogen, C1-6 halogenated alkyl, or phenyl, wherein the phenyl is optionally substituted with 1 or more halogen, —NR20R21, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkyloxy groups;
- R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, or C4-10 cycloalkenyl;
- R26 is hydrogen, cyclopentyl, or cyclohexyl;
- and pharmaceutically acceptable salts, and stereoisomers thereof.
6 more elements
Dependencies are inferred from the claim text.